PERS PE C T IV E

forever unprepared the predictable unpredictability of pathogens

Forever Unprepared The Predictable Unpredictability of Pathogens

Kent A. Sepkowitz, M.D. he recent behavior of two infamous pathogens methicillin-resistant Staphylococcus aureus (MRSA) and this winters preswine edition of influenza virus has proved an embarrassment to scientists everywhere. Both organisms have flouted the most basic tenet of the field of infectious disease, our bedrock belief that resistance to antimicrobial agents is caused by exposure to those same antimicrobial agents. It is our version of Newtons third law, that for each action there is an equal and opposite reaction. And on this assumption we have built the entire public health approach to preventing the emergence of drug resistance: we preach, if not demand, parsimony when giving antimicrobials. But we have been dead wrong not once, but twice with regard to these two old foes. Theoretically the defenders of public health, we infectious-disease specialists and public health prognosticators have been caught flat-footed: the appearance of community-acquired MRSA a few years ago and of oseltamivirresistant influenza virus earlier this year has shown us just how poorly we perform in predicting the next development in the microbial world. First, while we fixed our gaze on the slow and inexorable spread of MRSA through hospitals, a new strain was appearing in the community, seemingly out of nowhere. Meanwhile, we had readied ourselves for what we saw as the next inevitable advance in the march of S. aureus across the human population the appearance of vancomycin-resistant S. aureus (VRSA),
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which we had believed, logically enough, was nearing our doorstep. The related Enterococcus faecium had already found its way toward durable resistance to our old workhorse vancomycin, so forecasting that the next stop would be staphylococcus was hardly controversial. Indeed, VRSA infection has begun to occur, little by little, one extremely alarming case at a time. Surely its day will come but not just yet. The intensity of our concern and the frequency of the doomsday dispatches were appropriate. We were simply chasing the wrong microbe. It is community-acquired MRSA, not VRSA (or vancomycin intermediately resistant S. aureus, known as VISA), that now occupies the center of the public health stage. And just about everything predicted for VRSA has come true for community-acquired MRSA. Its everywhere; its deadly; it has changed the day-to-day management of skin infections and pneumonia in clinics, emergency rooms, and intensive care units. Its a true public health disaster. Its just a different disaster from the one we were exercised about, and equally important, its an organism with a mystifying pedigree. Where did it come from? No one is certain, but what seems clear is that it is very unlikely to be a feral descendant of hospital isolates.1 In other words, decades of hospital use, abuse, and overuse of antibiotics and generations of unwashed hands and improperly fastened hospital gowns did not create this brand of drug resistance. Rather, community-acquired MRSA appears
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to be responding to something fundamentally different from the familiar interactive push-and-pull cycle on which we had placed our bets. Ironically, the communityacquired pathogen now is spreading relentlessly into hospitals and clinics, behaving like any standard nosocomial MRSA and exploiting the same inattention to basic infection-control and containment measures. Meanwhile, this seasons act 1 of influenza virus proved even less predictable. During the winter, oseltamivir-resistant H1N1 influenza virus appeared at catastrophically high rates in the United States accounting for more than 95% of H1N1 influenza infections, up from 10% or so last year. Yet just as community-acquired MRSA seemed to have arisen without provocation, the occurrence of oseltamivirresistant influenza virus did not appear to be directly related to the overuse of oseltamivir. For example, as noted in a recent editorial, 67% of H1N1 strains in Norway are oseltamivir-resistant, though the antiviral drug is rarely used there, whereas in Japan, which has the worlds highest per capita oseltamivir use, H1N1 resistance rates are only 3%.2 Moreover, other circulating influenza strains, including the winters concurrent H3N1 strain and the subsequent novel H1N1 strain, remain fully susceptible to oseltamivir, providing further evidence that overuse of the antiviral drug did not drive the skyrocketing resistance. It appears that, just like community-acquired MRSA, oseltamivir-resistant influenza virus just happened:

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PE R S PE C T IV E

Forever Unprepared The Predictable Unpredictability of Pathogens

a mutation that may have been supported for other reasons has also conferred, as if accidentally, complete resistance against our lead antiviral drug. As with MRSA, our binoculars were directed elsewhere in this instance, on the looming threat of avian influenza or some other potent influenza virus resembling the one responsible for the catastrophic 1918 pandemic. True, the dispatches on bird flu were, and remain, mesmerizing. We have watched the wave of

Other than humility and a familiar lesson about the dangers of hubris, what can we learn from the sobering realities presented by these latest developments? First, preparation is an important and necessary activity, but in no way is it protective. One might even argue that it can have the negative consequence of lulling us into thinking we have a problem covered, when clearly we never do. The excited activity that the threat of an epidemic can evoke, including emergency meetings

Nothing microbes do, whether under the duress imposed by antimicrobials or from some less evident pressure, should surprise us. Its their world; we only live in it.
cases first in animals, then in humans move slowly across the globe: a few people in Indonesia, then a farm animal in Egypt. Like VRSA or VISA, avian influenza will surely eventually set up shop in North America, where affected birds have already been found, and cause disease in humans. But the winters first influenza crisis was one of drug resistance, not the avian disaster that was predicted, and the current novel H1N1 influenza outbreak was not on professional forecasters radar. Rather than reading about and worrying over the unceasing spread of oseltamivir-resistant H1N1 influenza across Scandinavia, too many of us were busy arguing over whether to stockpile a doomsday supply of oseltamivir to protect health care professionals and family members of patients. Here again, we simply missed the boat (though the extra cartons of oseltamivir were rather handy during the springs entanglement with the novel H1N1 influenza virus). and machinations and the hurried preparation of a guidance document, also may become an end and a professional satisfaction unto itself. In defense of this panic-driven approach, the product may not be entirely useless: preparation, albeit for the wrong invader, sharpens reflexes and can have at least some minimal practical yield, such as stockpiles of protective gear for health care workers. Second, we should marvel at the raw, restless power of microbes. They have the numbers trillions and quadrillions and more that replicate wildly, inaccurately, and disinterestedly. Nothing microbes do, whether under the duress imposed by antimicrobials or from some less evident pressure, should surprise us. Its their world; we only live in it. In this regard, it is perhaps fitting that our most successful incursion against them Flemings discovery of penicillin on a nearly discarded culture plate is immortalized as a fluke, an accident, the prodn engl j med 361;2 nejm.org july 9, 2009

uct of sloppy laboratory hygiene, anything but a headlong Manhattan Projectlike assault against the enemy. Finally, and perhaps most important, doctors should be reminded to keep our teachings out of church. Once again, it seems that our message against profligate use of antimicrobial agents has crept over into the realm of morality, that comic-book world of good guys and bad guys. Yes, overprescribing of antibiotics is an enormous problem that must be curtailed. It causes predictable problems, and its interruption results in predictable relief of drug resistance.3 But it is not a moral crisis, and scientists and clinicians are not Sundayschool teachers. Just as we must watch our waistlines and our bottom lines and not drink to excess and never exceed the speed limit, in the same spirit we must control runaway antibiotic use because it will help peoples health and save money but not because such restraint is holy or somehow separates good people from bad. In the future, we must resolve to keep fire and brimstone out of public health decisions. Otherwise, good judgment, necessary alertness, and scientific doubt also may go up in smoke.
No potential conflict of interest relevant to this article was reported. From the Memorial Sloan-Kettering Cancer Center, New York. 1. Chambers HF. The changing epidemiology of Staphylococcus aureus? Emerg Infect Dis 2001;7:178-82. 2. Weinstock DM, Zuccotti G. The evolution of influenza resistance and treatment. JAMA 2009;301:1066-9. 3. Seppl H, Klaukka T, Vuopio-Varkila J, et al. The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. N Engl J Med 1997;337:441-6.
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The New England Journal of Medicine Downloaded from www.nejm.org by LAURA VALDES CRUZ on November 30, 2010. For personal use only. No other uses without permission. Copyright 2009 Massachusetts Medical Society. All rights reserved.